Sharp pains shot
through the patient’s stomach, and he had constant diarrhea. Seven rounds of
antibiotics over 18 months had only made him feel worse. A previously
healthy man in his 20s who wishes to remain anonymous, he had contracted a
recurring case of Clostridium difficile, or C. diff, after
having his gallbladder removed in 2012. Hospital patients are prone to C.
diff since antibiotic treatment for other maladies decimates the
infection-fighting capacity of what scientists call the gut microbiome, the
trillions of cells that move through the human digestive system. “It didn’t
just affect my gut,” he says. “I was exhausted all the time. I had really bad
brain fog. I couldn’t concentrate.”
Desperate, he
researched possible therapies and discovered articles about fecal transplants
wiping out the infection. But his gastroenterologist refused to perform the
procedure. So he took matters into his own hands. He asked his roommate to
supply a stool sample, bought an enema kit from CVS, pulsed the mixture in a
blender, strained it through a coffee filter and pumped it into his gut. As
though a wizard had cast a spell, he made a full recovery within days.
Welcome to the most
promising new frontier in medicine: poop. By focusing on what’s coming out of
patients’ rear ends, a growing body of scientific research over the last 15
years has highlighted the crucial role the microbiome plays in human health.
That new understanding could lead to breakthrough treatments for a huge range
of illnesses, from obvious ones like digestive ailments and food allergies to
surprising ones like cancer and autism. A microbiome-derived drug is already in
the works to prevent childhood asthma.
“It’s only in the past 15 years that we’ve come to understand
the incredible diversity of the microbiome. It’s almost like a rainforest
inside our bodies. There are 100 times more bacterial genes than human genes,”
says Smith
Put crudely, the
idea is to use gut bugs as drugs. More than 50,000 scientific papers in the
last five years have explored the microbiome’s effects. Various kinds of gut
bacteria appear to stimulate or suppress immune responses in the body, while others
seem to fight off disease-causing microbes. A groundswell of cutting-edge
research has the potential to deliver a burst of new therapies that will vastly
reduce human suffering—and generate huge paydays for the field’s
pioneers.
When scientists
transferred gut microbiome cells from obese mice into lean ones, the recipients
gained weight. In one study, melanoma patients with the most
diverse microbiomes had the best response to immunotherapy. And mice injected with gut bacteria from marathon runners ran
longer distances. A new drug for obesity alone could be worth more
than $20 billion.
So far, the most
compelling microbiome-derived therapy is a live fecal transplant for C.
diff, which strikes half a million Americans annually, killing 15,000.
In 2013, the New England Journal of Medicine published a paper that caught the scientific
community by surprise and jump-started investment in microbiome drug
development. In a randomized trial, 94% of recurrent C. diff patients
recovered after receiving fecal transplants. To put that in context, cancer
drugs with efficacy rates as low as 10% have been approved by the FDA.
“I don’t think there’s any other field of medicine today that
holds as much promise for the future of medicine as the microbiome,” says Olle.
Billions of dollars
are pouring into microbiome medicine. Gbola Amusa, a medical doctor and partner
at Chardan, a health care–focused investment bank in New York, pegs the total
amount invested since 2014 at more than $5 billion. Techie billionaires including
Bill Gates, Salesforce founder Marc Benioff and Silicon Valley venture
capitalist Vinod Khosla are funding microbiome startups, and Gates, Benioff and
Mark Zuckerberg have all made donations to support microbiome research at
institutions including Stanford, Washington University in St. Louis and
the University of California, San Francisco.
The race is on for
FDA approval of the first drug made from gut bacteria. But the science is young
and unproven. At Oppenheimer in New York, Mark Breidenbach says investor
enthusiasm in microbiome companies is on a downswing because “there is no
consensus about what the microbiome can do.”
Amusa is more
bullish. “The science is turning,” he says. “When it comes through with proof,
these biotech companies will be worth not hundreds of millions of dollars, but
billions.”
Somerville, Massachusetts–based Finch
Therapeutics is one of the most promising startups developing
microbiome drugs. Cofounder Mark Smith, 33, was a microbiology grad student at
MIT when the 20-something C. diff patient begged him for help.
“I had to tell him, I’m a microbiologist, not a doctor,” Smith says.
The patient’s
ordeal motivated Smith to create OpenBiome,
the equivalent of a public blood bank for human feces, while Smith was still at
MIT in 2013. The Cambridge, Massachusetts, nonprofit, the first of its kind in
the world, has since supplied stool for more than 53,000 transplants in 1,200
hospitals and clinics.
Inspired by the
demand for transplants, Smith cofounded for-profit Finch (named for the diverse
group of finches Charles Darwin discovered in the Galápagos Islands) in 2016 to
develop an FDA-approved C. diff pill. Currently, most doctors
perform fecal transplants through a colonoscopy, which can cost as much as
$5,000. The procedure is not FDA-approved or reliably covered by
insurance.
Smith and his 80
employees occupy two floors in an industrial park that formerly housed
administrative offices and storage space for the Harvard Art Museums. Tall and
slender with piercing blue eyes, he welcomes the inevitable jokes that come
with being a human-feces entrepreneur. On Halloween he wore a poop-emoji
costume (“I was a pooper trooper”) to the office, where the copiers have names
like Squatty Potty and Magic Stool Bus.
But he has raised
serious capital. Venture funds have put in $130 million, and Finch has a
partnership with Tokyo-based pharma giant Takeda to develop drugs for
ulcerative colitis and Crohn’s disease, which together have 10 million
sufferers worldwide. Finch is also working on an autism drug.
Traditionally,
scientists start with data gathered through experiments on mice. Finch is
taking a “human-first” approach, skipping the rodents and analyzing the stool
of human patients who have recovered after receiving fecal transplants. “We’re
looking at what works in patients and figuring out how to make our drugs from
the top down,” Smith says. “It’s called reverse translation.”
For one of
its C. diff drugs, Finch is extracting what Smith describes as
the “full spectrum” of bacteria in a human stool sample from a patient who has
been successfully treated, freeze-drying it and delivering the equivalent of a
fecal transplant in a single pill. It’s also working on simpler drugs made from
five to 10 key bacteria. It expects results from its first Phase 2
trial (which demonstrates efficacy) of the full-spectrum C. diff capsule
by the end of the second quarter of 2020.
“Even if only a few
of the microbiome therapies scientists are working on come to fruition,” Smith
says, “it will have a huge impact on public health.”
Another MIT Ph.D., Bernat Olle, 40, is
running Vedanta
Biosciences, a nine-year-old Cambridge, Massachusetts–based
microbiome drug developer with $112 million in funding, including $10 million
from the Bill & Melinda Gates Foundation. The Gates investment supports
preclinical research at Vedanta aimed at developing a gut bacteria–derived drug
that would prevent child malnutrition in the developing world. Nearly
200 million children under age 5 suffer from either wasting or stunting, resulting
in at least 1.5 million deaths a year. “Malnourished children struggle to gain
weight even when fed enough,” Olle says. “Emerging research suggests that this
is because their gut microbiota develop abnormally, and that beneficial gut
bacterial strains may help correct this imbalance.”
Vedanta also has
two partnerships with big pharmaceutical companies, including Bristol-Myers
Squibb, to develop drugs aimed at boosting the effectiveness of immunotherapy
to treat melanoma and colorectal and gastric cancers. Like Finch, Vedanta is
developing a drug to treat recurrent C. diff.
Inside Vedanta’s
maze of labs and storage rooms is an oversized freezer containing fecal matter
from 275 donors on four continents, including an indigenous tribe in Papua New
Guinea. Vedanta is isolating and then testing bacteria from each sample in the hope
of determining which strains make the most effective drugs.
A wiry Catalan
immigrant with close-cropped salt-and-pepper hair who bicycles to work, Olle
came to the U.S. in 2002 to study chemical engineering at MIT, where he focused
on the emerging science of using live organisms like bacteria to produce drugs.
In 2007, after earning both an MIT doctorate and an MBA from the Sloan School,
he joined PureTech Health, a Boston biotech firm.
In 2010 PureTech
backed him in launching Vedanta with five cofounders, all scientists, including big
names such as Kenya Honda, a microbiology professor at Keio University medical
school in Tokyo. Honda had published a groundbreaking paper on the connection between gut bacteria and
regulatory T cells, known to prevent inflammatory diseases. “Think of them as
the U.N. peace forces of the intestine,” Olle says. “Honda’s work suggested
that the cells encoded in human DNA are influenced by the bacteria that live
within you.”
“This work has
forced me to rethink what it means to be human,” Olle says. “We are not just
the product of the Homo sapiens genome.”
Every gold rush attracts its share of
charlatans and claim jumpers. More than a half-dozen startups are using the
microbiome as a marketing buzzword to sell stool-analysis tests. The kits,
which require the consumer to mail a small sample to a lab, purport to convey
valuable personalized health data and nutrition advice. That despite a
consensus among scientists that it’s not yet possible to draw useful dietary
recommendations from a person’s poop. To avoid hostile oversight by the FDA,
the kit sellers are careful to make no specific claims about diagnosing or
treating particular diseases.
Four years ago,
former InfoSpace billionaire Naveen Jain, 60, launched Bellevue,
Washington–based Viome,
which sells a $119 “gut intelligence test” online. After analyzing a pea-sized
stool sample, it sends customers a customized 60-page report with dietary recommendations
“aimed at balancing your overall microbiome.” It might recommend, for instance,
increasing consumption of “superfoods” like alfalfa sprouts and anchovies or
avoiding green beans and kombucha. Jain says Viome has sold more than 100,000
kits and banked more than $15 million in revenue last year.
“Viome’s claims are
not supported by any scientific literature,” says Jonathan Eisen, a medical
microbiology professor who directs microbiome research at the University of
California, Davis. “What they’re saying is, in fact, deceptive.” A dozen former
Viome staffers say they believe the company was selling a product of dubious
value. Six of those ex-staffers describe the food recommendations as
“pseudoscience.”
“Anyone who says
this doesn’t understand how our science works and how we make recommendations,”
Jain counters. “It’s not my job to convince everyone; it’s my job to continue
to help make the world a better place.”
A nonstop talker
prone to enthusiastic, stream-of-consciousness self-promotion, Jain immigrated
to the U.S. from India in 1982 and worked at Microsoft from 1989 until 1996,
when he founded InfoSpace, also in Bellevue, which delivered internet content
to early cellphones. His net worth ballooned to $8 billion, then crashed to
$220 million when the first internet bubble burst. A flood of shareholder suits
followed, and the InfoSpace board fired him as CEO in late
2002. Before he left InfoSpace, he bought a $13 million stucco mansion on the
shores of Lake Washington not far from Jeff Bezos’ and Bill Gates’ pads.
Despite having no
background in science or medicine, Jain has managed to raise $75 million from
investors including Benioff and Khosla. Both declined to comment on their
microbiome investments. But Alex Morgan, a Khosla Ventures principal with an
M.D. and Ph.D. from Stanford, suggests Khosla’s decision to back Viome has
nothing to do with nutritional advice. Instead, he says, the firm invested
because Viome hired a team of scientists from the U.S. Department of Energy’s
Los Alamos National Laboratory. In addition, Viome had made a deal with the lab
to license a valuable tech platform that has a unique ability to sequence the
biochemical activity in microorganisms.
“The goal is to scientifically show that it’s not voodoo stuff
or a placebo,” says Jain
So even if Jain is
selling snake oil, Viome might have significant value. Indeed, British pharma
giant GlaxoSmithKline struck a royalty deal with Viome in November 2019 to use
its tech to help develop microbiome-derived vaccines. Jain’s investors could
make out handsomely.
At Caltech in Pasadena, California,
microbiologist Sarkis Mazmanian, 47, is considered one of the foremost gurus of
microbiome research. In 2012 the MacArthur
Foundation gave him a $500,000 “genius” grant for his work on
the microbiome’s role in disease. Since then, he’s been exploring one of the
most intriguing connections in human health: the “gut-brain axis.” The working
thesis is that the bugs in your belly have a direct impact on your neurological
health, which has profound implications for autism, Parkinson’s and
Alzheimer’s.
In 2008, two years
after joining the Caltech faculty, Mazmanian published a cover story in Nature that documented his successful treatment
of inflammatory bowel disease in mice with human gut bacteria. A Caltech
colleague, Paul Patterson, who was researching autism in mice, saw a possible
connection to the digestive problems suffered by as many as 60% of children with
autism.
Together they
started testing whether human gut bacteria could induce and ameliorate
autism-like symptoms in mice. In the midst of their early work, Patterson was
diagnosed with fatal brain cancer. In a hospital room at UCLA where Patterson
was awaiting surgery in May 2014, Mazmanian signed papers giving Patterson a
stake in a company that would develop drugs from their experiments. “I wanted
Paul to get the recognition of his contribution,” says Mazmanian. Patterson
died the following month.
Mazmanian is
carrying on their research in his sub-basement lab at Caltech, where 1,000
germ-free mice, delivered by Caesarean section in sterile conditions to ensure
they are bacteria-free, live inside plastic-encased rectangular bubbles. Grad
students douse the animals’ food with various gut microbes to test which
bacteria promote tremors and motor problems in mice that correlate with
Parkinson’s symptoms in humans.
In 2016, David
Donabedian, a chemistry Ph.D. who was then a partner at Longwood Fund, a Boston
venture capital firm, volunteered to raise the money and research power to move
Mazmanian’s biotech venture forward. The company, Waltham,
Massachusetts–based Axial Biotherapeutics, has $55 million in
backing and 30 employees. Under Donabedian as CEO, Axial is in the early stages
of developing synthetic drugs made of small molecules it hopes will absorb the
particular gut-bacteria byproducts (called “metabolites”) that appear to
exacerbate autism symptoms. It’s also working on a drug to treat the digestive
problems suffered by many people with Parkinson’s.
In the U.S., more
than a million people suffer from autism, and there are no drugs to treat it;
an additional million have Parkinson’s. What would be the value of an
FDA-approved drug for either condition? “I can’t give you a market size,” says
Donabedian. “But if either one hits, it will be huge.”
Chris Howerton, a
biotechnology analyst at Jefferies, a New York investment bank, is less shy.
“If every single microbiome paper turns into a proven therapy, it could impact
the drug markets for most major categories of disease, which together were
worth $350 billion in 2018 in the U.S. alone,” he says. “The breadth of the
microbiome’s potential application is really tantalizing.”
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